PMID: 9190287Feb 1, 1997Paper

FR900482, a close cousin of mitomycin C that exploits mitosene-based DNA cross-linking

Chemistry & Biology
R M WilliamsS B Rollins

Abstract

The class of antitumor antibiotics that includes FR900482 has a very close structural analogy to the mitomycins, one of which, mitomycin C, has been in widespread clinical use for more than 20 years. Like mitomycin C, these antitumor antibiotics are reductively activated in vivo and covalently cross-link DNA as a result of activity of the mitosene moiety generated on reduction. Owing to differences in structure and the attendant mechanistic differences in bioreductive activation between the mitomycins and FR900482, FR900482 does not produce an adventitious superoxide radical anion during reductive activation and thus does not exhibit oxidative strand scission of DNA. It is postulated that the low clinical toxicity of FR900482 relative to mitomycin C is a direct manifestation of the mechanistic differences of bioreductive activation leading to the highly reactive DNA cross-linking mitosenes. Using Fe(II)-EDTA footprinting, we showed that the two natural products FR900482 (1) and dihydro, FR66979 (3), and the semi-synthetically derived triacetate FK973 (2), display remarkable selectivity for 5' deoxy-CG sequences of DNA, and that this selectivity is abolished upon deletion of the exocyclic N2 amine of either participating guanosi...Continue Reading

Citations

Oct 7, 2006·Journal of Molecular Modeling·Anne-Marie Sapse, Duli C Jain
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Jan 3, 2012·The Journal of Organic Chemistry·Susan D Wiedner, Edwin Vedejs
Jan 24, 2009·Organic Letters·Stephen ChamberlandRobert M Williams
Sep 24, 1998·Journal of Biomolecular Structure & Dynamics·D Y LandoA A Akhrem
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Apr 13, 2004·The Journal of Organic Chemistry·Masashi SuzukiTohru Fukuyama
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